Project Summary ARID1A, encoding a subunit of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator across human cancers. Most notably, inactivating mutations in ARID1A occur in ~50% of ovarian clear cell carcinomas (OCCC) and ~30% of ovarian endometrioid carcinomas (OEC). There is an unmet need for effective treatment modalities for ARID1A-mutated ovarian cancers. For example, OCCC is generally refractory to standard agents used to treat epithelial ovarian cancer, and when diagnosed in advanced stages, OCCC carries the worst prognosis of all ovarian cancer subtypes. The overall goal of this proposal is to develop the first combinatorial targeted approach for ARID1A-mutated ovarian cancers with a durable outcome. We show that the inhibition of EZH2 is synthetically lethal with ARID1A mutation. We also show that ARID1A mutation is synthetically lethal with the inhibition of HDAC6. The objectives of this application are to investigate mechanisms underlying this newly discovered synthetic lethality and to investigate a combination therapeutic strategy for ARID1A-mutated ovarian cancer. Our central hypothesis is that targeting EZH2 and HDAC6 using clinically applicable small molecule inhibitors can achieve a durable therapeutic outcome for ARID1A-mutated ovarian cancer. Three Specific Aims are proposed: Aim 1 is to investigate the p53-dependent mechanism by which ARID1A-mutated ovarian cancer cells are selectively sensitive to the inhibition of HDAC6; Aim 2 will investigate the role of the SWI/SNF complex catalytic subunits switch in determining the sensitivity to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells; and Aim 3 will investigate the combinatorial therapeutic strategy for ARID1A-mutated ovarian cancer by simultaneously inhibiting HDAC6 and EZH2. The proposed studies are highly innovative because they challenge current research/clinical paradigms and utilize innovative methods to explore new intervention strategies for ARID1A-mutated ovarian cancers. The research proposed is of high impact because it has the potential to develop the first synthetic lethality-based, combinatorial therapeutic strategy for ARID1A-mutated ovarian cancer with a durable outcome. Since ARID1A is the most frequently mutated epigenetic regulator across human cancers, the mechanistic insights gained from the current studies will have broad implications for many different types of cancers as well.